Context

17α-Hydroxylase/17,20-lyase deficiency (17OHD) caused by mutations in the CYP17A1 gene is a rare form of congenital adrenal hyperplasia typically characterised by cortisol deficiency, mineralocorticoid excess and sex steroid deficiency.

Objective

To examine the phenotypic spectrum of 17OHD by clinical and biochemical assessment and corresponding in silico and in vitro functional analysis.

Design

Case series.

Patients and results

We assessed eight patients with 17OHD, including four with extreme 17OHD phenotypes: two siblings presented with failure to thrive in early infancy and two with isolated sex steroid deficiency and normal cortisol reserve. Diagnosis was established by mass spectrometry-based urinary steroid profiling and confirmed by genetic CYP17A1 analysis, revealing homozygous and compound heterozygous sequence variants. We found novel (p.Gly111Val, p.Ala398Glu, p.Ile371Thr) and previously described sequence variants (p.Pro409Leu, p.Arg347His, p.Gly436Arg, p.Phe53/54del, p.Tyr60IlefsLys88X). In vitro functional studies employing an overexpression system in HEK293 cells showed that 17,20-lyase activity was invariably decreased while mutant 17α-hydroxylase activity retained up to 14% of WT activity in the two patients with intact cortisol reserve. A ratio of urinary corticosterone over cortisol metabolites reflective of 17α-hydroxylase activity correlated well with clinical phenotype severity.

Conclusion

Our findings illustrate the broad phenotypic spectrum of 17OHD. Isolated sex steroid deficiency with normal stimulated cortisol has not been reported before. Attenuation of 17α-hydroxylase activity is readily detected by urinary steroid profiling and predicts phenotype severity.

Significance statement

Here we report, supported by careful phenotyping, genotyping and functional analysis, a prismatic case series of patients with congenital adrenal hyperplasia due to 17α-hydroxylase (CYP17A1) deficiency (17OHD). These range in severity from the abolition of function, presenting in early infancy, and unusually mild with isolated sex steroid deficiency but normal ACTH-stimulated cortisol in adult patients. These findings will guide improved diagnostic detection of CYP17A1 deficiency.

中文翻译：

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17α-羟化酶/17,20-裂解酶 (CYP17A1) 缺陷的广泛表型谱：病例系列

 语境

由CYP17A1基因突变引起的 17α-羟化酶/17,20-裂解酶缺乏症 (17OHD) 是一种罕见的先天性肾上腺增生症，典型特征为皮质醇缺乏、盐皮质激素过多和性类固醇缺乏。

 客观的

通过临床和生化评估以及相应的计算机和体外功能分析来检查 17OHD 的表型谱。

 设计

 案例系列。

 患者和结果

我们评估了 8 名 17OHD 患者，其中 4 名具有极端 17OHD 表型：两名兄弟姐妹在婴儿早期发育迟缓，两名兄弟姐妹患有孤立性类固醇缺乏症和正常皮质醇储备。通过基于质谱的尿类固醇分析确定诊断，并通过遗传CYP17A1分析进行确认，揭示纯合和复合杂合序列变异。我们发现了新的（p.Gly111Val、p.Ala398Glu、p.Ile371Thr）和先前描述的序列变体（p.Pro409Leu、p.Arg347His、p.Gly436Arg、p.Phe53/54del、p.Tyr60Ile fs Lys88X）。在 HEK293 细胞中采用过表达系统的体外功能研究表明，在两名皮质醇储备完整的患者中，17,20-裂解酶活性总是降低，而突变型 17α-羟化酶活性保留了 WT 活性的 14%。反映 17α-羟化酶活性的尿皮质酮与皮质醇代谢物的比率与临床表型严重程度密切相关。

 结论

我们的研究结果说明了 17OHD 的广泛表型谱。以前尚未报道过正常刺激皮质醇导致的孤立性类固醇缺乏症。通过尿类固醇分析很容易检测到 17α-羟化酶活性的减弱，并预测表型的严重程度。

 意义陈述

在仔细的表型、基因分型和功能分析的支持下，我们在此报告了由于 17α-羟化酶 (CYP17A1) 缺乏 (17OHD) 导致的先天性肾上腺增生患者的棱镜病例系列。这些症状的严重程度不等，从婴儿早期出现的功能丧失，到成年患者中单独性类固醇缺乏但 ACTH 刺激的皮质醇正常的异常轻微。这些发现将指导改进 CYP17A1 缺陷的诊断检测。